The basics

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is typically defined as two or more demyelinating events separated by both time and space. There are four basic categories of MS: relapsing remitting (RR-MS), secondary progressive (SP-MS), progressive relapsing (PR-MS) and worsening relapsing-remitting (WRR-MS, sometimes called chronic progression MS). The vast majority of patients suffer from RR-MS, which means that the patient experiences episodes of symptomatic disease followed by a return to normal function. Over the course of years, however, the level of neurological function gradually worsens in many patients and remission periods get progressively shorter. These patients then risk more severe, potentially permanent damage.

Demographically, multiple sclerosis typically affects young, white adults, especially of European descent. Those between the ages of 20-40 have shown the highest incidence of MS. In fact, a diagnosis of MS is rare in children or in patients over 60 years of age.

It's also more prevalent in temperate climates. More than half (60%) of MS patients are female. MS commonly affects the eyes early in the course of the disease, with the most common signs being optic neuritis and/or extraocular muscle disturbances.

Etiology

Although we do not know the exact cause of MS, it is believed that the principle predisposing defect may be a genetically determined defect in the immune response to viral exposure. This defect may interfere with the differentiation between the infecting virus and the body's CNS myelin. In this scenario, a viral infection in childhood induces an immune reaction against myelin, which manifests clinically when the patient is older.

During acute stages of inflammation, there is active destruction of the myelin sheath covering the nerve. This period is followed by some degree of tissue repair, which corresponds clinically to the relapsing-remitting course of MS. However, even during these quiet periods of clinical remission, recent research indicates that there is progressive deterioration of neur onal function on a histopathologic level.

If this course continues, individual axons will be permanently destroyed and the patent will present clinically with secondary-progressive MS.

This gradual progression is one of the reasons why early identification of demyelinating activity with timely intervention is important. Another reason: early intervention may significantly delay or prevent the resultant disability of clinically definite MS (CDMS).

On a cellular level, the classic CNS lesions of MS are distinct areas of demyelination (plaques), which are most commonly restricted to the white matter of the brain. These plaques tend to concentrate beneath the pia in the paraventricular area of the cerebrum, brain stem and spinal cord.

In addition, T-lympho-cytes and monocyte-macrophage cells play a role in active lesions. It's believed that these cells help cause the destruction of the myelin. Plaques that have become inactive (during quiet stages of the disease) have a different microscopic feature. In these cases, there is a fibral-like gliosis present where the myelin once was.

Diagnosing MS

The role of the optometrist is to correctly diagnose optic neuritis, explore the underlying risk of multiple sclerosis and refer. MS can present in different ways depending on where demyelination occurs. Common clinical features include decreased visual acuity, nystagmus, dysarthria, decrease in vibration perception and propioception, ataxia and intense tremor, weakness of one or more limbs, spasticity and bladder problems. Patients will often demonstrate periods of these activities, followed by periods of relative normalness.

In more advanced disease with brain stem involvement, the fifth cranial nerve is involved and the patient may exhibit facial hypesthesia and trigeminal neuralgia. If this involvement includes the seventh cranial nerve, a Bell's palsy or hemifacial spasm may be present. Vertigo, vomiting and nystagmus may occur when the vestibular division of cranial nerve VIII is involved. When cerebellar connections are involved, the patient will typically suffer from ataxia. The patient's stance and gait may also be affected, speech may become scanning in nature and an intention tremor may develop.

Patients who have suffered corticospinal deficits will demonstrate weakness, spasticity, hypereflexia, clonus, Babinski response and loss of abdominal skin reflexes. Loss of posterior column function will generally result in a loss of joint position sense and vibration sense, and will eventually lead to sensations of extremity tingling or tightness, and band-like sensations of the trunk. If the patient suffers spinothalamic track involve-ment, she will demonstrate a decrease in temperature sensations.

Additional signs and symptoms of cord demyelination are bladder or bowel dysfunction, impotence and an electric shock-like symptom when the neck undergoes flexion (Lhermitte's sign).

The examination of patient suspected of MS should include the following:

History. You should inquire about the specifics of any vision loss, such as whether the loss was accompanied by pain. Optic neuritis specifically features pain upon eye movement and an accompanying gradual loss of vision, which progresses over three to 10 days. Sudden vision loss that occurs on awakening is more likely caused by ischemia, and progressive, gradual vision loss existing for one month or longer is more likely to be caused by a compressive lesion.

Question the patient regarding any symptoms such as fatigue, Uhthoff symptom, L'Hermitte's sign (tingling at the base of the spine when flexing the neck), weakness, pain, tingling or numbness in the arms and legs, lack of coordination and any difficulties with bowel movement and urination.

Eye exam. Along with best-corrected visual acuity, you should check color vision, check for a relative afferent pupillary defect, and order threshold visual field testing. In addition, you should check specifically for ocular motility abnormalities such as internuclear ophthalmol-oplegia and nystagmus. Doing this will not only help you confirm a diagnosis, but it will also help you monitor for progress as the patient recovers from a particular episode.

Consult with Neurology. Any patient you suspect of having MS should be referred immediately to either a neurologist or neuro-ophthalmologist to assess the need for immunomodulatory medication and neuroimaging studies.

Neuroimaging

MRI is the most common and established technique for properly diagnosing and managing MS patients. An MRI can be used to help identify and monitor the glial and axonal destructive changes associated with MS. However, newer techniques are emerging which may be better-able to help MS patients. Among them are:

Magnetic resonance spectroscopy (MRS). This technique measures tissue levels of various metabolites, such as N-acetyl aspartate (NAA), and calculates the biochemical changes associated with MS. One study found that MRS corresponded well with the neurological disability associated with MS and concluded that it may be accurate in assessing axonal destruction.

Magnetization transfer imaging (MTI). This method utilizes a concept known as tissue water proton mobility to indirectly quantify myelin loss. MTI permits practitioners to quantify myelin volume throughout the entire brain and evaluate it as a function of neurological disability.

Management of MS

There are several drugs available which reduce the intensity, frequency and duration of the exacerbation of MS and/or the associated optic neuritis. However, none of them work consistently in all patients.

High-dose methylprednisolone disrupts the immune process that causes demyelination of the nerve by reducing production of harmful T-lymphocytes. In addition, this agent works to inhibit the release of cytokine, tumor necrosis factor and interferon-gamma. This dual action helps to reduce inflammation within the CNS and improve a patient's clinical symptoms.

High-dose systemic corticosteroids may also improve the blood-brain barrier, leukocyte activity or glial function.

Interferon-beta treatment. Avonex (interferon beta-1a; Biogen) and Rebif (interferon beta-1a, Serono) are recombinant interferon beta preparations that were created with amino acid sequences that are identical to natural human interferon beta. This differs from Betaseron (interferon beta-1b, Berlex Laboratories), which was created from Escherichia coli and was the first interferon analog approved for RR-MS.

In most cases, interferon beta treatment for acute MS is administered by both intramuscular and subcutaneous injection. Interferon-beta decreases T-cell activation and causes down regulation of immune cell mediators, notably interleukin-10.

The Controlled High Risk Avonex Multiple Sclerosis Prevention Study (CHAMPS) helped support the theory that early therapeutic intervention with Interferon ß-1A (Avonex) during the first clinical demyelinating episode may help some patients in delaying the development of clinically definite MS. In this study, CDMS developed in half of the placebo-treated patients but only in one-third of patients in the Avonex group — a 44% reduction.

In addition, the Avonex group demonstrated a slower increase in the volume of brain lesions and 57% fewer MRI lesions than the placebo. This study and others help foster the idea that early intervention may delay the emergence of CDMS and its accompanying debilitation.

Copaxone (glatiramer acetate, Teva Pharmaceutical). Copaxone is a polymer of four amino acids that mimic the constituency of myelin basic protein. It either produces antigen-suppressor cells specific for myelin basic protein (MBP), or it interferes with T-cell activation by competing with MBP for major histocompatibility complex binding sites responsible for antigen presentation. This agent is often helpful for patients in the early stages of the disease, with minimal clinical disability.

Other strategies. Some studies show intravenous cyclophosphamide and adrenocortictropic hormone(ACTH) helped halt the progression of chronic, progressive MS in one year. Other therapies sometimes used for symptomatic relief include baclofen and tizaidine for spasticity, propantheline or emepromium bromide for bladder symptoms, amitriptyline and fluoxetine hydrochloride for depression, and amantadine for fatigue.

On the horizon

There is a new agent called Antegren (natalizumab, Biogen), which is being investigated for the treatment of RR-MS and SP-MS. Natalizumab is a monoclonal antibody that binds to alpha 4 integrin. It is believed to help mediate the inflammatory process of MS. A recent study found that nine out of 10 patients demonstrated a reduction in new brain lesions after six months of therapy. There was also a significant reduction in relapse frequency and perception of well-being among the natalizumab group.

There's no getting around it

We optometrists must expand our roles as primary eyecare providers when managing patients with optic neuritis and/or the accompanying MS. Although these are not patients that we see routinely, they are still our patients and deserve our care.

References available on request.

Dr. Gupta practices full scope optometry in Stamford, Conn. He's also clinical director of The Center for Keratoconus at Stamford Ophthalmology. E-mail him at Deegup4919@hotmail.com.

Ms. Gupta is a clinical pharmacist who has years of both retail and hospital pharmacy experience.